Department of Vascular Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, P. R. China.
The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, P. R. China.
J Mater Chem B. 2022 Oct 5;10(38):7836-7846. doi: 10.1039/d2tb00474g.
Acute limb ischemia (ALI) is the most severe manifestation of peripheral artery disease, accompanied by pH/temperature-microenvironment changes in two different phases. In the acute phase, temperature and pH are significantly decreased, and reactive oxygen species (ROS) are excessively generated owing to the sharp reduction of blood perfusion. Afterwards, in the chronic phase, although the temperature gradually recovers, angiogenesis is delayed due to chronic vascular injury, skeletal muscle cell apoptosis and endothelial cell dysfunction. Current therapeutic strategies mainly focus on recanalization; however, their effects on scavenging ROS in the acute phase and promoting angiogenesis in the chronic phase are quite limited. Herein, an injectable pH and temperature dual-responsive poloxamer 407 (PF127)/hydroxymethyl cellulose (HPMC)/sodium alginate (SA)-derived hydrogel (FHSgel), encapsulating melatonin and diallyl trisulfide-loaded biodegradable hollow mesoporous silica nanoparticles (DATS@dHMSNs), is developed, which can intelligently respond to the different phases of ALI. In the acute phase of ischemia, the decreased pH results in the rapid release of melatonin to scavenge excessive ischemia-induced ROS. On the other hand, in the chronic repair phase, the recovered temperature triggers the sustained release of DATS@dHMSNs from the FHSgel, thus generating hydrogen sulfide (HS) to enhance the angiogenesis and microcirculation reconstruction of ischemic limbs.
急性肢体缺血（ALI）是外周动脉疾病最严重的表现形式，伴有两个不同阶段的 pH/温度微环境变化。在急性期，由于血液灌注急剧减少，温度和 pH 值显著降低，活性氧（ROS）过度生成。之后，在慢性期，尽管温度逐渐恢复，但由于慢性血管损伤、骨骼肌细胞凋亡和内皮细胞功能障碍，血管生成延迟。目前的治疗策略主要集中在再通上；然而，它们在清除急性期 ROS 和促进慢性期血管生成方面的效果相当有限。在此，开发了一种可注射的 pH 和温度双响应泊洛沙姆 407（PF127）/羟甲基纤维素（HPMC）/海藻酸钠（SA）衍生水凝胶（FHSgel），其中包封了褪黑素和二烯丙基三硫化物负载的可生物降解的中空介孔硅纳米粒子（DATS@dHMSNs），可智能响应 ALI 的不同阶段。在缺血的急性期，降低的 pH 值导致褪黑素迅速释放，以清除过多的缺血诱导的 ROS。另一方面，在慢性修复阶段，恢复的温度触发 FHSgel 中 DATS@dHMSNs 的持续释放，从而产生硫化氢（HS），增强缺血肢体的血管生成和微循环重建。
